Prostate cancer is the most common form of cancer in U.S. males and second only to lung cancer as the leading cause of mortality. Although several therapeutic options are available for early- stage, organ-confined tumors, hormonal therapy remains the primary, most effective mainstay therapy for the treatment of advanced disease. Despite the greater than 80 percent response rate to hormonal therapy, these tumors eventually progress into an "androgen-independent" (AI) state, and the survival of patients beyond this stage becomes very limited. Clearly, there is a need to develop pharmaceuticals that can prevent or retard the progression of these androgen-independent tumors. It has been documented that most androgen-independent prostate cancer cells continue to express or even overexpress the androgen receptor (AR), and that this receptor is still involved in their growth. Therefore, AR may still be a valid drug target for new therapies for the treatment of these AR-positive, hormone-refractory tumors. In the past few years, it has become clear that protein-protein interactions play an important regulatory role in nuclear receptor signaling. We have used the estrogen receptor (ER) as a model in previous studies and demonstrated that disruption of important protein-protein interactions can efficiently inhibit ER-mediated transcription. We believe a similar approach can also be applied to AR, and that targeting protein-protein interactions required for AR function will permit the identification of mechanistically- distinct drugs that can be used alone or with existing therapies for the treatment of AR-positive hormone-refractory prostate cancers. The objectives of this proposal are: (1) characterization of potential protein-protein interaction surfaces on the androgen receptor using combinatorial random peptide libraries; (2) identification of bona fide AR-interacting protein complexes using a proteomic approach; and, (3) validation of specific protein- protein interaction surfaces on AR as targets for the development of novel anti-androgens. We believe that in addition to identifying new drug targets for the treatment of prostate cancers, this research will provide insight into the cellular determinants of AR pharmacology.